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  • Milde, Till  (5)
  • Brain Neoplasms
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  • 1
    In: Pediatric Blood & Cancer, March 2018, Vol.65(3), pp.n/a-n/a
    Description: Infants with low‐grade glioma (LGG) and diencephalic syndrome have a poor outcome. The patient described here had a desmoplastic infantile astrocytoma harboring a BRAF V600E mutation. After relapse following initial standard chemotherapy treatment, he was successfully treated with the BRAF V600E inhibitor vemurafenib at the age of 3 years 11 months and 5 years 0 months. A rapid response was observed on both occasions. This illustrates the possibility of continuous oncogenic addiction and the therapeutic potential of BRAF V600E inhibitor monotherapy in LGG, even in very young severely compromised children. BRAF V600E inhibition in LGG and possible (re‐)treatment regimens are briefly discussed.
    Keywords: Braf V600e Inhibitor ; Child ; Desmoplastic Infantile Astrocytoma ; Infant ; Low‐Grade Glioma ; Vemurafenib
    ISSN: 1545-5009
    E-ISSN: 1545-5017
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  • 2
    In: Neuro-Oncology, 2017, Vol. 19(12), pp.1607-1617
    Description: BackgroundEmbryonal tumor with multilayered rosettes (ETMR) is a rare and aggressive embryonal brain tumor that solely occurs in infants and young children and has only recently been recognized as a separate brain tumor entity in the World Health Organization classification for CNS tumors. Patients have a very dismal prognosis with a median survival of 12 months upon diagnosis despite aggressive treatment. The aim of this study was to develop novel treatment regimens in a preclinical drug screen in order to inform potentially more active clinical trial protocols. MethodsWe have carried out an in vitro and in vivo drug screen using the ETMR cell line BT183 and its xenograft model. Furthermore, we have generated the first patient-derived xenograft (PDX) model for ETMR and evaluated our top drug candidates in an in vitro drug screen using this model. ResultsBT183 cells are very sensitive to the topoisomerase inhibitors topotecan and doxorubicin, to the epigenetic agents decitabine and panobinostat, to actinomycin D, and to targeted drugs such as the polo-like kinase 1 (PLK1) inhibitor volasertib, the aurora kinase A inhibitor alisertib, and the mammalian target of rapamycin (mTOR) inhibitor MLN0128. In xenograft mice, monotherapy with topotecan, volasertib, and actinomycin D led to a temporary response in tumor growth and a significant increase in survival. Finally, using multi-agent treatment regimens of topotecan or doxorubicin combined with methotrexate and vincristine, the response in tumor growth and survival was further increased compared with mice receiving single treatments. ConclusionsWe have identified several promising candidates for combination therapies in future clinical trials for ETMR patients.
    Keywords: Actinomycin D ; Brain Tumor ; Etmr ; Topotecan ; Volasertib
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 3
    In: Klinische Pädiatrie, 2018, Vol.230(06)
    In: Klinische Pädiatrie, 2018, Vol.230(06), pp.305-313
    Description: Central nervous system (CNS) tumors account for the highest mortality among pediatric malignancies. Accurate diagnosis is essential for optimal clinical management. The increasing use of molecular diagnostics has opened up novel possibilities for more precise classification of CNS tumors. We here report a single-institutional collection of pediatric CNS tumor cases that underwent a refinement or a change of diagnosis after completion of molecular analysis that affected clinical decision-making including the application of molecularly informed targeted therapies. 13 pediatric CNS tumors were analyzed by conventional histology, immunohistochemistry, and molecular diagnostics including DNA methylation profiling in 12 cases, DNA sequencing in 8 cases and RNA sequencing in 3 cases. 3 tumors had a refinement of diagnosis upon molecular testing, and 6 tumors underwent a change of diagnosis. Targeted therapy was initiated in 5 cases. An underlying cancer predisposition syndrome was detected in 5 cases. Although this case series, retrospective and not population based, has its limitations, insight can be gained regarding precision of diagnosis and clinical management of the patients in selected cases. Accuracy of diagnosis was improved in the cases presented here by the addition of molecular diagnostics, impacting clinical management of affected patients, both in the first-line as well as in the follow-up setting. This additional information may support the clinical decision making in the treatment of challenging pediatric CNS tumors. Prospective testing of the clinical value of molecular diagnostics is currently underway.
    Keywords: Brain tumor ; Molecular diagnostics ; Targeted therapy ; Cancer predisposition syndromes
    ISSN: 0300-8630
    E-ISSN: 1439-3824
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  • 4
    Language: English
    In: Acta Neuropathologica, 2016, Vol.131(6), pp.903-910
    Description: With the number of prognostic and predictive genetic markers in neuro-oncology steadily growing, the need for comprehensive molecular analysis of neuropathology samples has vastly increased. We therefore developed a customized enrichment/hybrid-capture-based next-generation sequencing (NGS) gene panel comprising the entire coding and selected intronic and promoter regions of 130 genes recurrently altered in brain tumors, allowing for the detection of single nucleotide variations, fusions, and copy number aberrations. Optimization of probe design, library generation and sequencing conditions on 150 samples resulted in a 5-workday routine workflow from the formalin-fixed paraffin-embedded sample to neuropathological report. This protocol was applied to 79 retrospective cases with established molecular aberrations for validation and 71 prospective cases for discovery of potential therapeutic targets. Concordance of NGS compared to established, single biomarker methods was 98.0 %, with discrepancies resulting from one case where a TERT promoter mutation was not called by NGS and three ATRX mutations not being detected by Sanger sequencing. Importantly, in samples with low tumor cell content, NGS was able to identify mutant alleles that were not detectable by traditional methods. Information derived from NGS data identified potential targets for experimental therapy in 37/47 (79 %) glioblastomas, 9/10 (90 %) pilocytic astrocytomas, and 5/14 (36 %) medulloblastomas in the prospective target discovery cohort. In conclusion, we present the settings for high-throughput, adaptive next-generation sequencing in routine neuropathology diagnostics. Such an approach will likely become highly valuable in the near future for treatment decision making, as more therapeutic targets emerge and genetic information enters the classification of brain tumors.
    Keywords: Medicine & Public Health ; Pathology ; Neurosciences ; Medicine;
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 5
    Language: English
    In: Oncotarget, 14 February 2017, Vol.8(7), pp.11460-11479
    Description: Pilocytic astrocytoma (PA) is the most frequent pediatric brain tumor. Activation of the MAPK pathway is well established as the oncogenic driver of the disease. It is most frequently caused by KIAA1549:BRAF fusions, and leads to oncogene induced senescence (OIS). OIS is thought to be a major reason for growth arrest of PA cells in vitro and in vivo, preventing establishment of PA cultures. Hence, valid preclinical models are currently very limited, but preclinical testing of new compounds is urgently needed. We transduced the PA short-term culture DKFZ-BT66 derived from the PA of a 2-year old patient with a doxycycline-inducible system coding for Simian Vacuolating Virus 40 Large T Antigen (SV40-TAg). SV40-TAg inhibits TP53/CDKN1A and CDKN2A/RB1, two pathways critical for OIS induction and maintenance. DNA methylation array and KIAA1549:BRAF fusion analysis confirmed pilocytic astrocytoma identity of DKFZ-BT66 cells after establishment. Readouts were analyzed in proliferating as well as senescent states, including cell counts, viability, cell cycle analysis, expression of SV40-Tag, CDKN2A (p16), CDKN1A (p21), and TP53 (p53) protein, and gene-expression profiling. Selected MAPK inhibitors (MAPKi) including clinically available MEK inhibitors (MEKi) were tested in vitro. Expression of SV40-TAg enabled the cells to bypass OIS and to resume proliferation with a mean doubling time of 45h allowing for propagation and long-term culture. Withdrawal of doxycycline led to an immediate decrease of SV40-TAg expression, appearance of senescent morphology, upregulation of CDKI proteins and a subsequent G1 growth arrest in line with the re-induction of senescence. DKFZ-BT66 cells still underwent replicative senescence that was overcome by TERT expression. Testing of a set of MAPKi revealed differential responses in DKFZ-BT66. MEKi efficiently inhibited MAPK signaling at clinically achievable concentrations, while BRAF V600E- and RAF Type II inhibitors showed paradoxical activation. Taken together, we have established the first patient-derived long term expandable PA cell line expressing the KIAA1549:BRAF-fusion suitable for preclinical drug testing.
    Keywords: Kiaa1549:Braf-Fusion ; Mapk-Inhibitors ; Oncogene-Induced Senescence (Ois) ; Pediatric Low Grade Glioma ; Pilocytic Astrocytoma ; Astrocytoma ; Brain Neoplasms ; Cell Culture Techniques ; Cell Line, Tumor ; Cellular Senescence -- Physiology
    E-ISSN: 1949-2553
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